Transdermal Fentanyl

PEP Topic

Chronic Pain

Description

Fentanyl is an opioid analgesic drug. The intent, in using a transdermal delivery system, is to allow passive diffusion of medication over a long period while maintaining a constant therapeutic dose. Transdermal fentanyl has been evaluated in terms of the management of chronic cancer-related pain and compared, in terms of opioid-related constipation, to opioids delivered by other routes.

Study Purpose:

To evaluate the efficacy and safety of transdermal fentanyl in the treatment of mucositis pain associated with chemotherapy

Intervention Characteristics/Basic Study Process:

Transdermal fentanyl (TF) was administered at a rate of 25 mcg/hour for adult patients, including those who were opioid naive. In pediatric patients, TF was administered at 12.5 mcg/hour. Because of the delayed effect of TF, patients received IV or subcutaneous morphine to relieve pain during the 8–12 hours after application of the patch. The dose of TF was adjusted after the first 24 hours, according to pain score, until pain was controlled. (Control was defined as a score of 3 or less on the rating scale.) The dose of TF was increased in 25 mcg/hour increments or 12.5 mcg/hour increments, according to age group. Severe breakthrough pain was managed with IV or subcutaneous morphine. All subjects were routinely treated with oral hygiene and antiviral, antibacterial, or antifungal oral agents. The same clinician evaluated patients on the first day of chemotherapy and daily for approximately three weeks. The patient reported pain daily by citing a score on a numeric scale. Mucositis was evaluated, on a daily basis, in terms of National Cancer Institute (NCI) Common Toxicity Criteria (CTC). Study questionnaires were sent to all patients. Questionnaire data were recorded before treatment with TF and 2, 6, and 10 days later.

Sample Characteristics:

The sample was composed of 32 patients.

Median patient age was 40 years. Age range was 4–76 years.

Of all patients, 56.3% were female and 43.7% were male.

The most common diagnoses were non-Hodgkin lymphoma, neuroblastoma, nasopharyngeal cancer, breast cancer, and small-cell lung cancer. Other diagnoses were included in the sample. All patients had a pain score of 4 or higher at study entry. All patients were receiving chemotherapy.

Setting:

Multisite

Outpatient

China

Study Design:

Open-label prospective trial

Measurement Instruments/Methods:

Numeric rating scale (NRS), to measure pain intensity

NCI CTC, to measure mucositis and adverse events

European Organization for Research and Treatment of Cancer Quality of Life questionnaire (EORTC QLQ-C30), to measure quality of life

Results:

After chemotherapy, median time to onset of moderate oral mucositis was five days (range of days to onset was 1–16).

Prior to use of TF, median NRS pain score was 6. By day 3 and at days 5, 7, 10, and 15, NRS scores had improved significantly (p < 0.001), compared to NRS scores at baseline. By day 3 median NRS was 4; by day 10, median NRS was 2. Pain disappeared in 65.6% of subjects.

Results as measured by the EORTC QLQ-C30 improved significantly (p < 0.001) in regard to appetite, mental status, sleep, fatigue, and daily life.

A dose of 25 mcg/hour was sufficient to control mucositis pain in 75% of the sample. Of all patients, 18.8% developed nausea and vomiting, 15.6% reported dizziness, 15.6% reported stomach discomfort, 6.3% reported constipation, and 6.3% reported patch-related itching.

No patients discontinued the drug because of toxicity.

Conclusions:

In this study, transdermal fentanyl was effective in reducing pain and improving quality-of-life parameters in the sample specified. Transdermal fentanyl was associated with a relatively low prevalence of adverse effects.

Limitations:

The study had a small sample, with fewer than 100 patients.

Authors did not state whether any patients required use of medication for breakthrough pain.

Authors did not report the prevalence of adverse effects by severity.

The number of pediatric patients versus adult patients was not stated. The means by which authors measured the pain and quality of life of very young patients (some as young as 4 years old) was not reported.

Other mechanisms for the management of oral mucositis, which could be expected to influence pain, were not controlled or fully described.

Nursing Implications:

Authors noted the delay of onset with TF opioid use. This delay suggests that TF therapy begin before onset of significant levels of pain. Further well-designed studies of TF, in adults and children, are needed.

Study Purpose:

To evaluate the effectiveness of transdermal fentanyl (TF) for pain management in patients with head and neck cancer receiving radiotherapy; to evaluate the effectiveness, safety, and long-term tolerability of TF after initial administration

Intervention Characteristics/Basic Study Process:

Patients entered in the trial were instructed in the use of TF. Initial TF dose was 25 mcg/hour, and patches were replaced every three days. Dose was titrated upward as needed, in 25 mcg/hour increments. Patients requiring more than 50 mcg/hour were allowed to use multiple patches to achieve the required dose. Doses greater than 100 mcg/hour were used in exceptional circumstances only. As a treatment for breakthrough pain, patients received immediate-release morphine to be administered as needed, every 2–4 hours. Use of all rescue medications was recorded. Pain was measured by means of a questionnaire that was administered at study entry and after 7, 14, 28, 35, and 42 days. Amount of rescue analgesics and data about constipation, diarrhea, and use of laxatives and antidiarrheals were recorded by patients daily. Investigators summarized the data at each study visit.

Sample Characteristics:

Initially, the sample was composed of 163 patients. The size of the sample at the end of the study was 108 patients.

Mean patient age of the final sample was 53 years. Age range was 24–68 years.

Of all patients, 9.2% were female and 90.8% were male.

All patients had head and neck cancer and were receiving radiation therapy. Most were taking nonsteroidal anti-inflammatory drugs, codeine, and tramadol. Of all patients, 11% were taking morphine at the time of study entry, and 57.7% were receiving chemotherapy. The average radiation dose over 42 days was slightly under 7000 cGy. Initial pain scores for 44.2% of patients were equal to or greater than 7.

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3, to measure adverse effects

Results:

The most commonly used dose of TF was 25 mcg/hour at days 0, 7, 14, 21, and 28.

Of patients treated by radiotherapy alone, 7% received a dose of TF that was larger than 25 mcg/hour. Of patients who also received chemotherapy, 34.8% required a dose larger than 25 mcg/hour.

VAS pain scores declined in all patients, but authors reported no statistical significance. By day 42, VAS scores indicated no further decline in pain.

Scores in each domain of the BPI improved after one week and on days 7 (p < 0.05) and 28 (p < 0.0001). BPI scores improved significantly.

Of patients in the initial sample, 55 patients (34.4%) had dropped out by the second week of treatment. They dropped out because of side effects. Twenty additional patients (12.3%) did not complete the study because of interruption of radiotherapy due to sepsis, the fact that TF was no longer needed, grade 3–4 vomiting (23.9%), nausea (16.6%), somnolence (4.9%), or dizziness (4.9%)

Conclusions:

Data suggest that TF can be effective and relatively easy to use, in an outpatient setting, for patients receiving radiotherapy; however, TF was accompanied by a high rate of severe side effects.

Limitations:

The study had a risk of bias due to no appropriate control group.

The study had a very high dropout rate due to side effects.

Authors provide no statistical analysis over time of VAS score changes or other score changes.

The reported findings related to side effects were confusing. Authors stated that, initially, 55 patients dropped out due to side effects and that another 20 patients did not complete the study. The actual prevalence and severity of side effects is unclear.

Nursing Implications:

Additional research regarding various approaches to pain management, in the cited population, is needed.

Study Purpose:

To investigate the efficacy and safety of fentanyl patches for pain relief after endoscopic submucosal dissection

Intervention Characteristics/Basic Study Process:

Patients were randomized to a fentanyl patch or placebo control group. Patients in the patch group were instructed in the use of the patch, which they applied the night before the procedure. Pain was assessed immediately before and immediately after the endoscopy. Maximum pain during the 24 hours following the endoscopy was assessed at discharge. All patients received IV propofol and cimetropium bromide during the procedure. Fentanyl patches used were 12 mcg patches.

Sample Characteristics:

The sample was composed of 104 patients.

Mean patient age was 62 years.

Of all patients, 71% were male and 29% were female.

Patients underwent a diagnostic endoscopy. Approximately two-thirds were diagnosed with dysplasia and one-third had early gastric cancer.

Setting:

Single site

Inpatient

South Korea

Phase of Care and Clinical Applications:

Phase of care: diagnostic

Study Design:

Randomized double-blind placebo-controlled trial

Measurement Instruments/Methods:

The study used a numeric rating scale to measure pain.

Results:

Prior to the procedure, there were no differences between groups in regard to pain rating.

Right after the endscopy, average pain rating with placebo was 5.17 and with the fentanyl patch, 4.26 (p = 0.03).

Maximum pain in the 24 hours after the procedure was slightly lower in those using fentanyl (p = 0.03) than in the placebo group. One day after the procedure, pain was lower in the patch group (1.20) versus those on placebo (2.98) (p < 0.001).

There were no differences between groups in regard to side effects.

Conclusions:

Findings show that fentanyl patches applied prior to endoscopic submucosal dissection are safe and effective in reducing postprocedural pain.

Limitations:

Authors did not describe unintended interventions or applicable interventions that would have influenced results.

Authors do not state whether patients on placebo received any medication for pain.

Nursing Implications:

Usual treatment for endoscopy pain can involve frequent injections. Since fentanyl patches can be applied prior to a procedure, they may provide more comfort than injected as-needed pain medications can. This study showed that, compared to placebo, a low-dose fentanyl patch applied prior to endoscopic dissection was effective in reducing pain and was not associated with adverse effects. The approach the study outlines is novel and may be applicable to various groups of patients who could experience acute pain.

Study Purpose:

To compare, in clinical practice, the effect and safety of a new matrix fentanyl patch (Fentanyl Improved Transdermal [FIT]) patch) to oral and other transdermal opioid treatment

Intervention Characteristics/Basic Study Process:

Patients were randomly assigned to either FIT patch or standard opioid treatment via oral or transdermal route. Morphine was the only rescue medication allowed. Patients could receive radiotherapy and chemotherapy as well as nonpharmacologic and pharmacologic pain management therapies. Patients randomized to FIT therapy switched from existing regimens to FIT therapy by means of standard conversion ratios. Patients had an initial screening visit and four additional visits. Each evening each patient assessed his or her pain and recorded the pain rating in a diary. Adverse events were monitored in follow-up visits through the 30-day trial period and for one week longer. Patients assessed adverse events on a four-point scale and recorded the rating.

Sample Characteristics:

The sample of patients who completed the trial was composed of 170 patients.

In the FIT group, mean patient age was 63.1 years (SD = 11.04 years). In the control arm, mean patient age was 61.3 years (SD = 11.66 years).

Of all patients, 40% were female and 60% were male.

Overall, 11% of patients randomized were opioid naive.

Authors did not report cancer diagnoses. All patients had a baseline Karnofsky performance score of 50 or higher.

Measurement Instruments/Methods:

Results:

There was no significant difference between groups regarding pain intensity ratings.

Subgroup analysis revealed no differences based on concomitant chemotherapy or radiotherapy or on subgroup analysis based on nocioceptive versus neuropathic pain.

Between groups, there were no significant differences in the prevalence or severity of adverse effects.

Authors observed no new or unexpected adverse drug reactions.

Conclusions:

Results showed no differences, in terms of pain management or adverse effects, between the new transdermal patch and standard transdermal or oral opioid treatment. Findings suggest that the new type of patch is safe and, in terms of efficacy, similar to standard treatments.

Limitations:

The study has a risk of bias due to no appropriate control group.

Authors provided no analysis of other medications or approaches used for pain management. (These were not controlled in the study.) Authors did not report analysis of morphine use for breakthrough pain.

Patients' diaries were the source of adverse events and pain intensity scores. Note, however, that authors stated that patients' records regarding rescue medication, for example, could not have been accurate. If patients' records were inaccurate, the study should have provided objective or observer scoring.

Nursing Implications:

Transdermal fentanyl, delivered by means of conventional patch or FIT patch, is an effective means of controlling cancer pain.

Study Purpose:

To facilitate dose escalation of strong opioids by using an opioid-tramadol combination

Intervention Characteristics/Basic Study Process:

Of 70 patients, 35 were treated conventionally, with increasing transdermal fentanyl (group F). The other 35 patients received oral tramadol added to their fentanyl before each increment of their transdermal opioid (group T). Patients started fentanyl therapy by taking 25, 50, 75, or 100 mcg/hour, the amount based on equianalgesic dosing. Maximum tramadol dose was 400 mg/day. Rectal tramadol was not used.

Sample Characteristics:

The sample was composed of 70 patients with intractable cancer pain whose visual analog pain score was greater than 3.

All patients were receiving palliative care and not in the active treatment phase of disease.

Setting:

The study was conducted in Italy.

Study Design:

Randomized open-label, prospectively evaluated study

Measurement Instruments/Methods:

Authors used a visual analog scale (VAS) to measure pain.

Results:

In group F, 33 patients completed the study; in group T, 34 patients completed the study.

Pain was equal in both groups; VAS scores did not differ. However, pain control in the tramadol group was achieved at slower escalation of fentanyl dose. The combination of a strong opioid with a weak opioid, to treat severe cancer pain, allowed a more gradual increase of analgesic delivery. Therefore, the combination minimized periods of overdosing and underdosing.

Application time for patches was significantly higher in group T. In group T, no patient's fentanyl patch dose changed before the patient reached the maximum tramadol dose of 400 mg per day.

Regarding adequacy of treatment, patients’, relatives’, and physicians’ judgments did not differ.

Conclusions:

The combination of a strong opioid and a weak opioid, to treat severe cancer pain, allowed a more gradual increase of analgesic delivery. Therefore, the combination treatment minimized periods of overdosing and underdosing. Combination treatment as specified is a useful alternative, especially when disease and pain progress quickly.

Limitations:

Severe nausea and vomiting occurred in six patients in group T and three in group F, possibly due to a synergistic effect between fentanyl and tramadol. This study was insufficiently powered to show statistically significant differences relating to uncommon or serious side effects.

Nursing Implications:

The greater number of fentanyl dose changes associated with higher fentanyl consumption in group F may support the hypothesis that tolerance is a pharmacologic effect, rather than a result of the rapid progression of disease. Additional study of the synergistic effect of tramadol and fentanyl, with respect to severe nausea and vomiting, is needed.

Study Purpose:

To compare, in patients with advanced cancer, the analgesic efficacy, adverse effects, and effect on quality of life of morphine, fentanyl, and methadone

Intervention Characteristics/Basic Study Process:

Patients were randomized to morphine, fentanyl, or methadone. Morphine was offered as breakthrough pain medication at one-sixth the equianalgesic 24-hour dose. Adjuvant medications were allowed. If the patient experienced poor opioid response or uncontrolled adverse events, he or she switched to another opioid. Data were collected at four weekly intervals.

Sample Characteristics:

The sample was composed of 108 patients, 36 in the morphine group (22 patients in this group completed the study), 36 in the fentanyl group (25 completed the study), and 36 in the methadone group (23 completed the study).

In the morphine group, mean patient age was 59 years; in the fentanyl group, 57 years; and in the methadone group, 61 years.

In the morphine group, 10 patients were female; in the fentanyl group, 14 were female; and in the methadone group, 12 were female. In the morphine group, 12 patients were male; in the fentanyl group, 11 were male; and in the methadone group, 11 were male.

Patients had advanced cancer with pain and required first-line opioids for pain control. Patients were excluded from the study if they had liver or renal disease, cognitive impairment, or expected survival of less than three months; if they were undergoing radiation therapy or a new course of chemotherapy; or if they had prevalent incident pain, mixed pain, or nociceptive and neuropathic pain. Breast cancer was the most frequent diagnosis.

Setting:

Multisite

Outpatient

Multiple sites in Italy

Study Design:

Randomized controlled trial

Measurement Instruments/Methods:

Scale (0 = not at all, 3 = severe), to measure adverse events

Number of passages per day, to measure constipation

Scale, 0–10, to measure pain intensity (PI)

Number of daily dose changes to stabilization

Opioid escalation index, or OEI (OMD – OSD/OSD per day x 100, where OMD represents doses administered at four weeks after study initiation and OSD represents the opioid starting dose at study initiation)

Spitzer Quality of Life Index

Costs of opioid therapy

Results:

A similar number of patients in each group switched to other opioids.

No significant differences existed in number of days to achieve dose stabilization.

No significant differences existed in the number of dose changes needed during titration.

No differences existed in the PI of the three groups.

OEI% was highest in the fentanyl group and significantly lower in the methadone group; 14 patients on methadone did not have a dose change, but 8 required a decrease in the dose and then a subsequent increase.

Conclusions:

All three opioids were effective in controlling cancer pain in some patients. Adverse event profiles were similar. Methadone was less expensive than fentanyl or morphine but required clinical expertise in dosing. (The doses of some patients had to decrease and then increase.)

Limitations:

The study had a small sample, with fewer than 100 patients.

The sample was a convenience sample; it was not blinded.

Nursing Implications:

Long-acting morphine, fentanyl, and methadone are effective in controlling the pain of advanced cancer. Methadone is an option for patients for whom cost is a concern. Prescribing methadone requires clinical expertise.

Study Purpose:

To evaluate the safety, efficacy, and pharmacokinetic profile of a 12.5 mcg/hour transdermal matrix fentanyl patch used to manage the persistent pain of patients with cancer

Intervention Characteristics/Basic Study Process:

On study day 1, the patch was applied. It was replaced every 3 days for a 10-day period. All patients initially received the 12.5 mcg/hour dose. At the time of patch replacement, the dose could be increased according to pain intensity and rescue medication used. Use of opioid receptor antagonist analgesics and other opioid medication was prohibited. Patients received fast-acting morphine for breakthrough pain. Serum fentanyl levels were measured on days 4, 7, and 10. Physicians assessed global effect on day 10 or at the time of study discontinuation. Patients provided a global assessment on days 1, 4, and 7.

Sample Characteristics:

The sample was composed of 85 patients.

Of all patients, 75% were age 60 or older. The age range was 40 to older than 70.

Of all patients, 47% were female and 53% were male.

Diagnoses included gastrointestinal cancer (which 40% of patients had), gynecologic cancer (10.6%), and hepatobiliary cancer (5.9%). The sample contained a mix of other cancer sites. At baseline, 69.4% of patients were taking oxycodone, 29.4% were taking morphine, and 1.2% were undergoing fentanyl injections for pain control.

Results:

In 78 patients, a total of 316 adverse events occurred. The most frequent adverse events were nausea (which 36% of patients experienced), somnolence (30.2%), vomiting (25.6%), diarrhea (19.8%), constipation (16.3%), pyrexia (12.8%), and insomnia (10.5%). Three patients experienced evere adverse events: dyspnea and respiratory failure. Authors observed 12 cases of skin irritation at the patch site. Of all patients, 96% reported that they were satisfied or very satisfied with the 12.5 mcg/hour transdermal matrix fentanyl patch. According to global assessment by physicians, the 12.5 mcg/hour transdermal matrix fentanyl patch was as effective as the other treatments in 98% of cases.

Conclusions:

The 12.5 mcg/hour transdermal matrix fentanyl patch appears to be a reasonable means of controlling persistent cancer pain in patients switching from low-dose morphine or oxycodone.

Limitations:

The study had a small sample, with fewer than 100 participants.

The study had a risk of bias due to no control or comparison group.

Authors provided no specific severity rating of adverse effects.

Distribution of final fentanyl doses associated with efficacy was not provided.

Authors did not report how adverse events were defined or recorded.

Authors did not report the use rescue medications.

Authors stated the results of a visual analog scale over time; however, they did not describe the scale or how it was used.

Study Purpose:

To evaluate the compliance to radiation treatment planning of patients with bone metastases who have been premedicated with transdermal fentanyl

Intervention Characteristics/Basic Study Process:

Fentanyl was delivered at 25–50 mcg/hour starting a week before treatment planning and during simulation. Immobilization devices were not mandatory.

Sample Characteristics:

The sample was composed of 42 enrolled patients.

Mean patient age was 68.5 years.

Of all patients, 16 were male and 26 were female.

Patients had epithelial cancer with skeletal metastases and strong pain uncontrolled by FANS and/or steroids. The most common primary cancers were breast and prostate cancers. All patients had 1–4 metastatic bone sites.

Median pain score at first evaluation was 12 (the range of scores was 4–36), mean Karnofsky Performance Status Score was 60 (range, 40–80). In the sample were 47 treated metastases: 27 vertebral bodies, 11 of the femur, 3 of the humerus, and one of the pelvis.

Patients were excluded if they had bone fractures or spinal cord compression; if estimated life expectancy was longer than three months; or if they did not have brain metastases.

Included subjects with moderate to severe cancer pain and who had a defined opiate need at study entry.

Compared slow-release oral morphine to transdermal opiates.

Studies were excluded if information about randomization was inadequate, the study did not report safety data, the sample included patients who needed opiate titration at study entry, or the study used historical controls or was a phase 2 trial.

Literature Evaluated:

The search retrieved 117 studies. Twelve studies were considered potentially eligible. Four were included in analysis.

Authors evaluated study quality by means of the Jadad scale. Two of the studies were of low quality, with a Jadad score of 2 or less.

Sample Characteristics:

The sample for meta-analysis consisted of four studies, which included 425 patients. Of the 425 patients, 188 were treated with transdermal fentanyl and 26 received buprenorphine.

Conclusions:

Limitations:

This meta-analysis had a small sample size.

Of the four studies in the meta-analysis, the quality of two studies was low. View findings with caution.

Nursing Implications:

Compared to slow-release oral morphine, transdermal opiates appear to be associated with fewer cases of constipation; transdermal opiates may be a better alternative for pain control in patients with constipation. This review suggests that patients may prefer pain medication via the transdermal route. Clinicians should consider constipation and preference in individualizing pain management.

Literature Evaluated:

Of the 117 trials retrieved, 11 were considered potentially eligible. The analysis included five trials. Three trials included patients with cancer, and two included patients without cancer. The quality of the reports was evaluated using the Jadad scale.

Sample Characteristics:

The studies reported on a total sample of 1,309 patients across all trials.

The sample included 652 patients who were treated with transdermal fentanyl and 657 who were treated with slow-release oral morphine.

The sample included 373 patients who were treated for cancer pain.

In some trials, patients were in palliative care programs.

Results:

Compared to slow-release oral morphine, transdermal fentanyl was associated with less constipation, urinary retention, and laxative use, as well as higher patient preference.

Slow-release oral morphine was associated with less nausea, diarrhea, and sweating.

Authors observed no significant differences between the two drugs in regard to overall safety or gastrointestinal safety, somnolence, anorexia, vomiting, hypoventilation, insomnia, or uncontrolled pain that called for opiate rescue doses.

Findings were stable following analysis of cancer and noncancer subgroups.

Conclusions:

Side-effect profiles of transdermal fentanyl and oral slow-release morphine differ, but in this analysis authors observed no significant differences in overall side effects and patient preference regarding the two approaches. Transdermal fentanyl appears to be a valid alternative to oral opiates.

Limitations:

The analysis included a small number of studies.

Two trials included in this evaluation were of low quality.

Not all trials used the same methods of equianalgesia.

Nursing Implications:

Findings should be interpreted with caution, given the limitations of this meta-analysis. Additional research comparing transdermal and other medication delivery routes for pain control is warranted. Transdermal opiates may be particularly useful for patients using opiate switching. Addressing individual patients' needs and concerns may mean that side-effect profiles play an important role in the selection of a medication delivery route.

Wootten, M. (2004). Morphine is not the only analgesic in palliative care: Literature review. Journal of Advanced Nursing, 45(5), 527–532.

Sample Characteristics:

Conclusions:

The evidence does show encouraging results with use of fentanyl, methadone, and ketamine. Transdermal fentanyl is recommended for those with stable pain because it is difficult to titrate quickly. All of these strong opioids were well tolerated and seemed to be comparable to morphine.